Sustained release small molecule drug formulation

ABSTRACT

An injectable depot formulation includes a biocompatible polymer, an organic solvent combined with the biocompatible polymer to form a viscous gel, and a small molecule drug incorporated in the viscous gel such that the formulation exhibits an in vivo release profile having C max  to C min  ratio less than 200 and lag time less than 0.2.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a Continuation of Ser. No. 13,790,930 filed Mar. 8,2013, which is a Continuation Ser. No. 11/535,398, filed Sep. 26, 2006,which claims benefit of provisional Application No. 60/722,845, filedSep. 30, 2005. The disclosures of Ser. Nos. 13/790,930 and 11/535,398are expressly incorporated by reference herein in their entireties.

BACKGROUND OF TIE INVENTION

The invention relates generally to delivery of small molecule drugs.

The term “small molecule drug,” as used herein, refers to beneficialagents having low molecular weight. The beneficial agents are usuallysynthesized by organic chemistry, but may also be isolated from naturalsources such as plants, fungi, and microbes. The common routes fordelivering small molecule drugs are oral, injection, pulmonary, andtransdermal.

Many psychotherapeutic drugs are small molecule drugs and are usuallyprovided as oral pills or bolus injections that can be administered oneor more times daily. However, oral pills and bolus injections may not beoptimal routes for administering small molecule psychotherapeutic drugsbecause of the peaks and troughs observed in plasma concentration afterdosing. Adverse effects and loss of therapeutic effect have beenassociated with plasma concentration peaks and troughs, respectively.

From the foregoing, psychotherapy as well as other forms of therapypresently relying on small molecule drugs administered in the form oforal pills and bolus injections may benefit from a sustained releasedosage form designed to minimize variations in plasma concentrationfollowing dosing. Administration of psychotherapeutic agents assustained release formulations will also increase patient compliance.

BRIEF SUMMARY OF THE INVENTION

In one aspect, the invention relates to an injectable depot formulationwhich comprises a biocompatible polymer, an organic solvent combinedwith the biocompatible polymer to form a viscous gel, and a smallmolecule drug incorporated in the viscous gel such that the formulationexhibits an in vivo release profile having C_(max) to C_(min) ratio lessthan 200 and lag time less than 0.2.

In another aspect, the invention relates to a method of administering asmall molecule drug to a subject in a controlled manner which comprisesimplanting in the subject an effective amount of an injectable depotformulation comprising a biocompatible polymer, an organic solventcombined with the biocompatible polymer to form a viscous gel, and asmall molecule drug incorporated in the viscous gel such that theformulation exhibits an in vivo release profile having C_(max) toC_(min) ratio less than 200 and lag time less than 0.2.

Other features and advantages of the invention will be apparent from thefollowing description.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows influence of drug salt form on in vivo release profile offormulations according to embodiments of the invention.

FIG. 2 shows influence of solvent type on in vivo release profile offormulations according to embodiments of the invention.

FIG. 3 shows influence of polymer type on in vivo release profile offormulations according to embodiments of the invention.

FIG. 4 shows formulations having near zero-order release profilesaccording to embodiments of the invention.

DETAILED DESCRIPTION OF THE INVENTION

The invention will now be described in detail with reference to a fewpreferred embodiments, as illustrated in accompanying drawings. In thefollowing description, numerous specific details are set forth in orderto provide a thorough understanding of the invention. However, it willbe apparent to one skilled in the art that the invention may bepracticed without some or all of these specific details. In otherinstances, well-known features and/or process steps have not beendescribed in detail in order to not unnecessarily obscure the invention.The features and advantages of the invention may be better understoodwith reference to the drawings and discussions that follow.

The invention is based in part on the discovery that incorporation of asparingly soluble small molecule drug in a depot gel vehicle produces asmall molecule drug formulation that has near zero-order release invivo. The release profile shows minimal lag time and burst. For a depotformulation, this release profile is surprising because the prevailingthought in the art is that a low burst, near zero-order release isvirtually impossible to attain unless special steps are taken, such ascoatings for drugs and microencapsulation. Several small drugformulations have been identified in this invention with in vivo releaseprofiles having a C_(max) to C_(min) ratio less than 200 and lag time,T_(lag), less than 0.2.

The variable “C_(min)” is the minimum drug concentration in plasma orserum. The variable “C_(max)” is the maximum drug concentration inplasma or serum. The variable “T_(lag)” is the ratio of T_(valley) toT_(total), where T_(valley) is less than T_(total). The variable“T_(valley)” is the time to reach C_(valley). The variable “C_(valley)”is the first trough of drug concentration in plasma or serum duringrelease. The variable “T_(total),” is the total release duration.

Small molecule drug formulations according to embodiments of theinvention can be prepared as depot injections. The environment of use isa fluid environment and may include a subcutaneous, intramuscular,intramyocardial, adventitial, intratumoral, or intracerebral portion, awound site, or tight joint spaces or body cavity of a human or animal.Multiple or repeated injections may be administered to the subject, forexample, when the therapeutic effect of the drug has subsided or theperiod of time for the drug to have a therapeutic effect has lapsed orwhen the subject requires further administration of the drug for anyreason. The formulation serves as an implanted sustained release drugdelivery system after injection into the subject. Such controlledrelease can be over a period of one week, more than one week, one month,or more than one month. Preferably, the controlled release is over atleast a period of one week, more preferably over a period of at leastone month.

A small molecule drug formulation according to an embodiment of theinvention includes a depot gel vehicle. The depot gel vehicle includes abiocompatible polymer, i.e., a polymer that would not cause irritationor necrosis in the environment of use. Biocompatible polymers that maybe useful in the invention may be bioerodible, i.e., graduallydecompose, dissolve, hydrolyze and/or erode in situ. Examples ofbioerodible polymers include, but are not limited to, polylactides,polyglycolides, polycaprolactones, polyanhydrides, polyamines,polyurethanes, polyesteramides, polyorthoesters, polydioxanones,polyacetals, polyketals, polycarbonates, polyorthocarbonates,polyphosphazenes, succinates, poly(malic acid), poly(amino acids),polyvinylpyrrolidone, polyethylene glycol, polyhydroxycellulose,polysaccharides, chitin, chitosan, and copolymers, terpolymers andmixtures thereof. The polymer is typically present in the depot gelvehicle in an amount ranging from about 5 to 80% by weight, preferablyfrom about 20 to 70%, often from about 40 to 60% by weight.

In one embodiment, the polymer is a polylactide. A polylactide polymeris a polymer based on lactic acid or a copolymer based on lactic acidand glycolic acid. The polylactide polymer can include small amounts ofother comonomers that do not substantially affect the advantageousresults that can be achieved in accordance with the invention. The term“lactic acid” includes the isomers L-lactic acid, D-lactic acid,DL-lactic acid, and lactide. The term “glycolic acid” includesglycolide. The polymer may have a lactic-acid to glycolic-acid monomerratio of from about 100:0 to 15:85, preferably from about 60:40 to75:25, often about 50:50. The polylactide polymer has a number averagemolecular weight ranging from about 1,000 to about 120,000, preferablyfrom about 5,000 to about 30,000, as determined by gel permeationchromatography. Suitable polylactide polymers are availablecommercially.

The depot gel vehicle further includes a biocompatible solvent whichwhen combined with the polymer forms a viscous gel, typically exhibitingviscosity in a range from 500 poise to 200,000 poise, preferably fromabout 1,000 poise to 50,000 poise. The solvent used in the depot gelvehicle is typically an organic solvent and may be a single solvent or amixture of solvents. To limit water intake by the depot gel vehicle inthe environment of use, the solvent, or at least one of the componentsof the solvent in the case of a multi-component solvent, preferably haslimited miscibility with water, e.g., less than 7% by weight, preferablyless than 5% by weight, more preferably less than 3% by weightmiscibility with water. Examples of suitable solvents include, but arenot limited to, benzyl benzoate (BB), benzyl alcohol (BA), ethylbenzoate (EB), triacetin, and N-methyl-2-pyrrolidone (NMP). The solventis typically present in the depot gel vehicle in an amount ranging fromabout 20 to 95% by weight, preferably in an amount ranging from about 30to 80% by weight, often in an amount ranging from about 40 to 60% byweight.

A formulation according to an embodiment of the invention includes asmall molecule drug dispersed or dissolved in a depot gel vehicle asdescribed above. The term “dispersed or dissolved” is intended toencompass all means of establishing the presence of the small moleculedrug in the viscous gel and includes dissolution, dispersion,suspension, and the like. Small molecule drugs used in formulations ofthe invention are sparingly soluble in water. In a preferred embodiment,small molecule drugs used in formulations of the invention have lessthan 1 mg/ml solubility in water. In one embodiment, small moleculedrugs used in formulations of the invention have a molecular weight in arange from 200 to 2,000 Daltons. Small molecule drugs used informulations of the invention may have a narrow or wide therapeuticwindow. However, the invention generally delivers salubrious results interms of C_(max) and toxicity control for small molecule drugs having anarrow therapeutic window. The small molecule drug is typically presentin the formulation in an amount ranging from about 1 to 50% by weight,more preferably in an amount ranging from about 5 to 40% by weight,often in an amount ranging from about 10 to 30% by weight.

In one embodiment, a small molecule drug formulation includes a smallmolecule psychotherapeutic drug, such as a small molecule antipsychotic,dopamine receptor agonist, dopamine receptor antagonist, serotoninreceptor agonist, serotonin receptor antagonist, and serotonin uptakeinhibitor drug. Table 1 below shows physiochemical properties of somesmall molecule psychotherapeutic drugs. R209130-base has the molecularformula C₁₉H₂₀FNO. R209130-mandelic acid salt (R209130) has themolecular formula C₁₉H₂₀FNO.C₈H₈O₃. R209130-tartaric acid salt (R167154)has the molecular formula C₁₉H₂₀FNO.C₄H₆O₆. R209130 and its analogspossess putative atypical antipsychotic properties and have demonstratedantianxiety, antidepressive, and socializing effects in animal models.These characteristics may be attributed to R209130 dual antagonism ofcentral dopamine D₂ receptors, serotonin 5-HT_(2A) and 5-HT_(2C)receptors, and the inhibition norepinephrine uptake. Risperidone-basehas the molecular formula C₂₃H₂₇FN₄O₂. Risperidone-pamoate has themolecular formula C₂₃H₂₇FN₄O₂.C₂₃H₁₆O₆. Risperidone is a combinedserotonin (5-HT₂) and dopamine (D2) receptor antagonist.

TABLE 1 Risperidone Risperidone Property R209130 R167154 R209130 basebase pamoate pKa 9.2 9.2 9.2 8.2/3.1 8.2/3.1 Solubility in 0.32 (pH 4.9)41.84 (pH 3.4) 0.008 (pH 9.5) 0.09 (pH 8.8) 0.2 (pH 7.2) H₂O (mg/ml)Solubility at 0.35  6.1 (pH 6.5) 2 1 0.2 (pH 7.2) pH 7 (mg/ml)Solubility in 58.6 at 40° C. 10.3 at 40° C. >200,000 32,000 50 BB(μg/ml) Solubility in  7.3 at 40° C. 41.3 at 40° C. >200,000 407 2.97 BA(mg/ml) Intrinsic 0.054 3.7 0.7 0.0025 N/A dissolution rate (mg/cm² ·min) LogP 3.9 4.0 N/A 3.04 N/A (C₈OH/pH 7 buffer) Molecular 449.5 447.5297.4 410.5 798.5 weight

A study was conducted to determine the PK profile of a small moleculedrug delivered from a depot gel vehicle according to the invention andthe influence of salt form of the drug, solvent type, polymer type,polymer molecular weight, polymer/solvent ratio, drug loading, andparticle size on the PK profile.

The following examples are presented for illustration purposes and arenot intended to limit the invention as otherwise described herein.

Example 1

A depot gel vehicle was prepared as follows: A HDPE container was taredon a Mettler PJ3000 top loader balance. Poly D,L-lactide-co-glycolide(PLGA), (L/G ratio of 50/50), available as RESOMER® RG 502 (PLGA-502),was weighed into the container. The container containing PLGA-502 wastared, and the corresponding solvent was added to the PLGA-502. Amountsexpressed as percentages for various combinations of PLGA-502 andsolvent are set forth below in Table 2. A hybrid mixer was used to mixthe PLGA-502 and solvent mixture, resulting in a clear gel-like solutionof the polymer in the solvent.

TABLE 2 PLGA-502 Benzyl Benzoate Benzyl Alcohol Formulation (wt %, g)(wt %, g) (wt %, g) A 50.067 50.044 B 50.023 24.988 24.988 C 50.36545.093 5.1780 D 50.139 37.553 12.560 E 50.350 45.193

Additional depot gel vehicles were prepared with solvents, selected frombenzyl benzoate (BB), benzyl alcohol (BA), ethyl benzoate (EB), ethylhydroxide (EtOH), triacetin, and N-methyl-2-pyrrolidone (NMP), andmixtures thereof, and polymers, selected from Poly D,L-lactide,available as RESOMER® L 104, RESOMER® R 104, RESOMER® 202, RESOMER® 203,RESOMER® 206, RESOMER® 207, RESOMER® 208; PLGA, L/G ratio of 50/50,available as RESOMER® RG 502H; PLGA, L/G ratio of 50/50, available asRESOMER® RG 503; PLGA, UG ratio of 50/50, available as RESOMER® RG 755;Poly L-lactide, molecular weight of 2000, available as RESOMER® L 206,RESOMER® L 207, RESOMER® L 209, RESOMER® L 214; PolyL-lactide-co-D,L-lactide, L/G ratio of 90/10, available as RESOMER® LR209; PLGA, UG ratio of 75/25, available as RESOMER® RG 752, RESOMER® RG756, PLGA, L/G ratio of 85/15, available as RESOMER® RG 858; PolyL-lactide-co-trimethylene carbonate, L/G ratio of 70/30, available asRESOMER® LT 706, and Poly dioxanone, available as RESOMER® X210(Boehringer Ingelheim Chemicals, Inc. Petersburg, Va.);DL-lactide/glycolide (DL), L/G ratio of 100/0, available as MEDISORB®Polymer 100 DL High, MEDISORB® Polymer 100 DL Low; DL-lactide/glycolide(DL), L/G ratio of 85/15, available as MEDISORB® Polymer 8515 DL High,MEDISORB® Polymer 8515 DL Low; DL-lactide/glycolide (DL), L/G ratio of75/25, available as MEDISORB® Polymer 7525 DL High, MEDISORB® Polymer7525 DL Low; DL-lactide/glycolide (DL), L/G ratio of 65/35, available asMEDISORB® Polymer 6535 DL High, MEDISORB® Polymer 6535 DL Low;DL-lactide/glycolide (DL), L/G ratio of 54/46, available as MEDISORB®Polymer 5050 DL High, MEDISORB® Polymer 5050 DL Low, MEDISORB® 5050Polymer DL 2A(3), MEDISORB® 5050 Polymer DL 3A(3), MEDISORB® 5050Polymer DL 4A(3) (Medisorb Technologies International L.P., Cincinnati,Ohio); and PLGA (L/G ratio of 50/50), PLGA (L/G ratio of 65/35), PLGA(L/G ratio of 75/25), PLGA (L/G ratio of 85/15), Poly D,L-lactide, PolyL-lactide, Poly glycolide, Poly e-caprolactone, PolyD,L-lactide-co-caprolactone (L/C ratio of 25/75), and PolyD,L-lactide-co-caprolactone (L/C ratio of 75/25), available fromBirmingham Polymers, Inc., Birmingham, Ala. Polycaprolactone-glycolicacid-lactic acid copolymer (PCL-GA-LA) was also used either mixed withpolyvinylpyrrolidone (PVP) or by itself. Typical molecular weights ofthese polymers are in the range of 6,000 to 20,000.

Example 2

Drug particles were prepared as follows: R209130, R167154, risperidonebase, or risperidone pamoate drug was passed through sieves of differentsizes to obtain drug particles having a certain range of particle sizedistribution. Particles in the range of 20 to 63 Am, 63 to 125 μm, 75 to125 μm, or less than 38 μm were obtained. Micronized particles receivedwere also used as drug particles.

Example 3

Depot formulations were prepared as follows: sieved drug particlesprepared as described in Example 2 were added into the depot gelvehicles prepared as described in Example 1 in an amount of 0 to 50% byweight and blended manually until the drug particles were wettedcompletely. Then, the mixture of drug particles and depot gel wasthoroughly blended by conventional mixing using a Caframo mechanicalstirrer with an attached square-tip metal spatula. Final homogeneous gelformulations were transferred to 3, 10, or 30 cc disposable syringes forstorage or dispensing.

Example 4

A representative number of implantable gels were prepared in accordancewith the foregoing procedures and tested in vivo in rats to determinerelease of the drug as determined by blood serum or plasma concentrationof drug as a function of time.

In general, in vivo studies in rats were performed following an openprotocol to determine plasma levels of the drug (e.g., R209130, R167154,risperidone base, risperidone pamoate) upon systemic administration ofthe drug via the implant systems of the invention. Depot gelformulations containing the drug, prepared as described in the Examplesabove, were loaded into 0.5 cc disposable syringes. Disposable needles(18 gauge) were attached to the syringes and heated to 37° C. using acirculator bath. The depot gel formulations were injected into rats.Blood was drawn at specified time intervals and analyzed for drugcontent. All plasma samples were stored at 4° C. prior to analysis.

Example 5

This example investigates influence of drug salt form on in vivo releaseof small molecule drugs from depot gel vehicles.

Particles of R209130 and R167154, in appropriate size range, wereincorporated in depot gel vehicles, as per procedure in Example 3.Resulting formulations are illustrated in Table 2 below. Finalhomogeneous depot formulations were transferred to 3, 10, or 30 ccdisposable syringes for storage or dispensing. In vivo release of thedrugs were analyzed, as per procedure in Example 4. In vivo releaseprofiles of the formulations are shown in FIG. 1. C_(max) to C_(min)ratio and T_(lag) of the formulations are shown in Table 2. R167154 andR209130 are different salt forms of the same drug. Formulation 7(R209130) has C_(max) to C_(min) ratio of 19.2 and T_(lag) of 0.61,while formulation 3 (R167154) has C_(max) to C_(min) ratio of 25.7 andT_(lag) of 0.33. This example shows that in vivo release is influencedby salt form of the formulation. Even though T_(lag) for formulation 7(R209130) is higher than T_(lag) for formulation 3 (R167154),formulation 7 appears to have better release rate profile and durationof release in comparison to formulation 3.

TABLE 2 PLGA BA BB Triacetin Drug C_(max)/ No. (wt %) (wt %) (wt %) (wt%) (wt %) C_(min) T_(lag) 3^(2,a,II,α,A) 45 22.5 22.5 0 10 25.7 0.337^(1,a,II,α,B) 45 22.5 22.5 0 10 19.2 0.61 1 = R209130, 2 = R167154, 3 =risperidone base, 4 = risperidone pamoate; a = 50/50 PLGA-502 (MW =16,000), b = 50/50 PLGA-502H (MW = 11,000), c = 50/50 PLGA (MW = 6400),d = 40/55/5 PCL-GA-LA (MW = ~13,500), e = 75/25 PLGA (MW = 14,300), f =80/20 PCL-GA-LA/PVP, g = RG502:RG502H (1:1); α = P/S ratio of 50/50, β =P/S ratio of 40/60, χ = P/S ratio of 45/55, δ = P/S ratio of 60/40, ε =P/S ratio of 55/45; A = 63-125 μm, B = 20-63 μm, C = 75-125 μm, D = <38μm, E = micronized, F = as is, G = not applicable; NV = no valley

Example 6

This example investigates influence of solvent type on in vivo releaseof small molecule drugs from depot gel vehicles.

Depot gel vehicles were prepared with PLGA-502 and a solvent selectedfrom BA, BB, EB, EtOH, NMP, and triacetin, and combinations thereof, asper procedure in Example 1. The depot gel vehicles were loaded with drugsubstance, in appropriate range, as per procedure in Example 3.Resulting formulations are illustrated in Table 3 below. Finalhomogeneous depot formulations were transferred to 3, 10 or 30 ccdisposable syringes for storage or dispensing. In vivo release profilesof the formulations in Table 3 are shown in FIG. 2. C_(max) to C_(min)ratio and T_(lag) of the formulations are shown in Table 3.

TABLE 3 Target content in formulation (% w/w) C_(max)/ No. PLGA BA BBEtOH NMP Triacetin EB Drug C_(min) T_(lag) 2^(2,a,II,α,A) 45 0 45 0 0 00 10 59.86 NV 3^(2,a,II,α,A) 45 22.5 22.5 0 0 0 0 10 25.68 0.3310^(1,a,III,α,C) 40 40 0 0 0 0 0 20 4.35 0.61 14^(1,a,III,α,C) 40 20 200 0 0 0 20 3.15 0.50 63^(3,a,VII,α,C) 43.3 0 0 0 0 43.3 0 13.4 1364.430.14 73^(3,a,VII,α,G) 43.3 0 0 0 0 0 43.3 13.4 5.20 N/A 1 = R209130, 2 =R167154, 3 = risperidone base, 4 = risperidone pamoate, a = 50/50PLGA-502 (MW = 16,000), b = 50/50 PLGA-502H (MW = 11,000), c = 50/50PLGA (MW = 6400), d = 40/55/5 PCL-GA-LA (MW = ~13,500), e = 75/25 PLGA(MW = 14,300), f = 80/20 PCL-GA-LA/PVP, g = RG502:RG502H (1:1); α = P/Sratio of 50/50, β = P/S ratio of 40/60, χ = P/S ratio of 45/55, δ = P/Sratio of 60/40, ε = P/S ratio of 55/45; A = 63-125 μm, B = 20-63 μm, C =75-125 μm, D = <38 μm, E = micronized, F = as is, G = not applicable; NV= no valley

In Table 3 above, formulation 63 (risperidone base/PLGA/triacetin depot)has a C_(max) to C_(min) ratio of 1364.64. On the other hand,formulation 73 (risperidone base/PLGA/EB depot) has a C_(max) to C_(min)ratio of 5.20, which is significantly lower than the C_(max) to C_(min)ratio for formulation 63. Formulation 2 (R167154/PLGA/BB depot) has aC_(max) to C_(min) ratio of 59.68. On the other hand, formulation 3(R167154/PLGA/BA/BB) has a C_(max) to C_(min) ratio of 25.68, which isless than half the C_(max) to C_(min) ratio for formulation 2. Thisindicates that solvent type can influence in vivo release profile of theformulation.

Example 7

This example investigates influence of polymer type on in vivo releaseof small molecule drugs from depot gel vehicles.

Depot gel vehicles were prepared with different polymers and loaded withR209130, in appropriate size range, as per procedure in Example 3.Resulting formulations are illustrated in Table 4 below. Finalhomogeneous depot formulations were transferred to 3, 10 or 30 ccdisposable syringes for storage or dispensing. Table 4 shows C_(max) toC_(min) ratio and T_(lag) for in vivo release profiles of theformulations. FIG. 3 shows in vivo release profiles of formulations inTable 4.

TABLE 4 Target content in formulation (% w/w) No. Polymer BA BB DrugC_(max)/C_(min) T_(lag) 22^(1,a,IV,α,C) 35 35 0 30 9.86 0.1723^(1,a,IV,α,C) 35 0 35 30 6.83 0.17 24^(1,a,IV,α,E) 35 0 35 30 44.0 NV25^(1,c,IV,α,C) 35 0 35 30 29.49 0.45 32^(1,d,IV,α,C) 35 0 35 30 10.650.12 33^(1,f,IV,α,C) 35 0 35 30 6.35 0.14 34^(1,a,IV,α,C) 35 35 0 308.75 0.23 35^(1,c,IV,α,C) 35 0 35 30 44.21 NV 48^(1,c,IV,α,E) 35 0 35 30163.12 NV 53^(1,e,IV,α,E) 35 0 35 30 31.16 0.25 59^(1,d,IV,α,C) 35 0 3530 6.26 0.07 1 = R209130, 2 = R167154, 3 = risperidone base, 4 =risperidone pamoate, a = 50/50 PLGA-502 (MW = 16,000), b = 50/50PLGA-502H (MW = 11,000), c = 50/50 PLGA (MW = 6400), d = 40/55/5PCL-GA-LA (MW = ~13,500), e = 75/25 PLGA (MW = 14,300), f = 80/20PCL-GA-LA/PVP, g = RG502:RG502H (1:1); α = P/S ratio of 50/50, β = P/Sratio of 40/60, χ = P/S ratio of 45/55, δ = P/S ratio of 60/40, ε = P/Sratio of 55/45; A = 63-125 μm, B = 20-63 μm, C = 75-125 μm, D = <38 μm,E = micronized, F = as is, G = not applicable; NV = no valley

Example 8

This example investigates influence of molecular weight of polymers onin vivo release of small molecule drugs from depot gel vehicles.

Depot gel vehicles were prepared with polymers with different molecularweights and loaded with drug substance, in appropriate size range, asper procedure in Example 3. Resulting formulations are illustrated inTable 5 below. Final homogeneous depot formulations were transferred to3, 10 or 30 cc disposable syringes for storage or dispensing. Table 5shows C_(max) to C_(min) ratio and Tag for in vivo release profiles ofthe formulations.

TABLE 5 Target content in Formulation (% w/w) Tri- No. PLGA BA BB acetinDrug C_(max)/C_(min) T_(lag) 10^(1,a,III,α,C) 40 40 0 0 20 4.35 0.6111^(1,a,III,α,D) 40 40 0 0 20 12.06 0.61 12^(1,a,IV,α,C) 35 35 0 0 304.78 0.14 13^(1,a,IV,α,D) 35 35 0 0 30 5.29 0.36 21^(1,c,III,α,C) 40 400 0 20 48.55 No valley 25^(1,c,IV,α,C) 35 0 35 0 30 29.49 0.4526^(1,c,IV,α,D) 35 0 35 0 30 41.67 No valley 48^(1,c,IV,α,E) 35 0 35 030 163.12 No valley 49^(1,c,IV,δ,E) 42 0 28 0 30 66.31 0.3963^(3,a,VII,α,C) 43.3 0 0 43.3 13.4 1364.43 0.14 64^(4,c,VIII,α,C) 36.90 36.9 0 26.1 11.66 No valley 69^(4,a,VIII,α,E) 36.9 0 36.9 0 26.1 14.120.90 70^(4,c,VIII,α,C) 36.9 0 36.9 0 26.1 22.11 no valley72^(3,a,VII,α,G) 43.3 0 43.3 0 13.4 24.48 N/A 1 = R209130, 2 = R167154,3 = risperidone base, 4 = risperidone pamoate, a = 50/50 PLGA-502 (MW =16,000), b = 50/50 PLGA-502H (MW = 11,000), c = 50/50 PLGA (MW = 6400),d = 40/55/5 PCL-GA-LA (MW = ~13,500), e = 75/25 PLGA (MW = 14,300), f =80/20 PCL-GA-LA/PVP, g = RG502:RG502H (1:1); α = P/S ratio of 50/50, β =P/S ratio of 40/60, χ = P/S ratio of 45/55, δ = P/S ratio of 60/40, ε =P/S ratio of 55/45; A = 63-125 μm, B = 20-63 μm, C = 75-125 μm, D = <38μm, E = micronized, F = as is, G = not applicable; NV = no valley

Example 9

This example investigates influence of polymer/solvent ratios on in vivorelease of small molecule drugs from depot gel vehicles.

Depot gel vehicles were prepared with different polymer/solvent ratiosand loaded with drug substance, in appropriate size range, as perprocedure in Example 3. Resulting formulations are illustrated in Table6 below. Final homogeneous depot formulations were transferred to 3, 10or 30 cc disposable syringes for storage or dispensing. Table 6 showsC_(max) to C_(min) ratio and T_(lag) for in vivo release profiles of theformulations.

TABLE 6 Target content in Formulation (% w/w) No. PLGA BB EtOH DrugC_(max)/C_(min) T_(lag) 22^(1,a,IV,α,C) 35 0 0 30 9.86 0.1723^(1,a,IV,α,C) 35 35 0 30 6.83 0.17 24^(1,a,IV,α,E) 35 35 0 30 44.00 NV25^(1,c,IV,α,C) 35 35 0 30 29.49 0.45 26^(1,c,IV,α,D) 35 35 0 30 41.67NV 27^(1,c,IV,β,C) 28 42 0 30 54.16 NV 28^(1,c,IV,β,D) 28 42 0 30 120.74NV 29^(1,a,IV,χ,C) 31.5 34.65 3.85 30 1.93 NV 30^(1,a,IV,χ,D) 31.5 34.653.85 30 7.07 0.29 48^(1,c,IV,α,E) 35 35 0 30 163.12 NV 49^(1,c,IV,δ,E)42 28 0 30 66.31 0.39 52^(1,e,IV,β,E) 28 42 0 30 47.86 NV53^(1,e,IV,α,E) 35 35 0 30 31.16 0.25 56^(1,b,IV,ε,F) 38.5 31.5 0 3017.10 NV 65^(4,c,VIII,α,E) 36.9 36.9 0 26.1 50.87 NV 66^(4,c,VIII,ε,G)40.6 33.2 0 26.1 38.39 NV 67^(4,c,VIII,ε,G) 33.2 40.6 0 26.1 43.55 NV 1= R209130, 2 = R167154, 3 = risperidone base, 4 = risperidone pamoate, a= 50/50 PLGA-502 (MW = 16,000), b = 50/50 PLGA-502H (MW = 11,000), c =50/50 PLGA (MW = 6400), d = 40/55/5 PCL-GA-LA (MW = ~13,500), e = 75/25PLGA (MW = 14,300), f = 80/20 PCL-GA-LA/PVP, g = RG502:RG502H (1:1); α =P/S ratio of 50/50, β = P/S ratio of 40/60, χ = P/S ratio of 45/55, δ =P/S ratio of 60/40, ε = P/S ratio of 55/45; A = 63-125 μm, B = 20-63 μm,C = 75-125 μm, D = <38 μm, E = micronized, F = as is, G = notapplicable; NV = no valley

Example 10

This example investigates influence of drug loading on in vivo releaseof small molecule drugs from depot gel vehicles

Depot gel vehicles were prepared with varying percentages of drug, inappropriate size range, as per procedure in Example 3. Resultingformulations are illustrated in Table 7 below. Final homogeneous depotformulations were transferred to 3, 10 or 30 cc disposable syringes forstorage or dispensing. Table 7 shows C_(max) to C_(min) ratio andT_(lag) for in vivo release profiles of the formulations.

TABLE 7 Target content in Formulation (% w/w) Formulation No. PLGA BA BBDrug C_(max)/C_(min) T_(lag) 4^(1,a,II,α,B) 45 45 0 10 4.37 0.505^(1,a,III,α,B) 40 20 20 20 10.66 0.61 7^(1,a,II,α,B) 45 22.5 22.5 1019.17 0.61 10^(1,a,III,α,C) 40 40 0 20 4.35 0.61 11^(1,a,III,α,D) 40 400 20 12.06 0.61 12^(1,a,IV,α,C) 35 35 0 30 4.78 0.14 13^(1,a,IV,α,D) 3535 0 30 5.29 0.36 14^(1,a,III,α,C) 40 20 20 20 3.15 0.5015^(1,a,III,α,D) 40 20 20 20 9.60 0.61 16^(1,a,IV,α,C) 35 17.5 17.5 307.16 0.61 17^(1,a,IV,α,D) 35 17.5 17.5 30 17.35 0.36 18^(1,a,V,α,C) 3030 0 40 3.54 0.39 1 = R209130, 2 = R167154, 3 = risperidone base, 4 =risperidone pamoate, a = 50/50 PLGA-502 (MW = 16,000), b = 50/50PLGA-502H (MW = 11,000), c = 50/50 PLGA (MW = 6400), d = 40/55/5PCL-GA-LA (MW = ~13,500), e = 75/25 PLGA (MW = 14,300), f = 80/20PCL-GA-LA/PVP, g = RG502:RG502H (1:1); α = P/S ratio of 50/50, β = P/Sratio of 40/60, χ = P/S ratio of 45/55, δ = P/S ratio of 60/40, ε = P/Sratio of 55/45; A = 63-125 μm, B = 20-63 μm, C = 75-125 μm, D = <38 μm,E = micronized, F = as is, G = not applicable; NV = no valley

Example 11

This example investigates influence of drug particle size on in vivorelease of small molecule drugs from depot gel vehicles.

Depot gel vehicles were prepared and loaded with drug particles inappropriate size range, as per procedure in Example 3. Resultingformulations are illustrated in Table 8 below. Final homogeneous depotformulations were transferred to 3, 10 or 30 cc disposable syringes forstorage or dispensing. Table 8 shows C_(max) to C_(min) ratio andT_(lag) for in vivo release profiles of the formulations.

TABLE 8 Target content in Formulation (% w/w) Formulation No. PLGA BA BBDrug C_(max)/C_(min) T_(lag) 7^(1,a,II,α,B) 45 22.5 22.5 10 19.17 0.6110^(1,a,III,α,C) 40 40 0 20 4.35 0.61 11^(1,a,III,α,D) 40 40 0 20 12.060.61 23^(1,a,IV,α,C) 35 0 35 30 6.83 0.17 24^(1,a,IV,α,E) 35 0 35 3044.00 NV 25^(1,c,IV,α,C) 35 0 35 30 29.49 0.45 26^(1,c,IV,α,D) 35 0 3530 41.67 NV 64^(4,c,VIII,α,C) 36.9 0 36.9 26.1 11.66 NV65^(4,c,VIII,α,E) 36.9 0 36.9 26.1 50.87 NV 66^(4,c,VIII,ε,G) 40.6 033.2 26.1 38.39 NV 72^(3,a,VII,α,G) 43.3 0 43.3 13.4 24.48 N/A 1 =R209130, 2 = R167154, 3 = risperidone base, 4 = risperidone pamoate, a =50/50 PLGA-502 (MW = 16,000), b = 50/50 PLGA-502H (MW = 11,000), c =50/50 PLGA (MW = 6400), d = 40/55/5 PCL-GA-LA (MW = ~13,500), e = 75/25PLGA (MW = 14,300), f = 80/20 PCL-GA-LA/PVP, g = RG502:RG502H (1:1); α =P/S ratio of 50/50, β = P/S ratio of 40/60, χ = P/S ratio of 45/55, δ =P/S ratio of 60/40, ε = P/S ratio of 55/45; A = 63-125 μm, B = 20-63 μm,C = 75-125 μm, D = <38 μm, E = micronized, F = as is, G = notapplicable; NV = no valley

Example 12

A formulation is described as near zero-order if the ratio of C_(max) toC_(min) is less than 200, preferably less than 50, more preferably lessthan 30. T_(lag) in release of formulation is preferably less than 0.2.Formulations that do not show C_(valley) do not exhibit lag. Table 9shows a number of formulations that exhibited the characteristic nearzero-order release. FIG. 4 shows in vivo release profiles of selectedformulations in Table 9.

TABLE 9 Target content in Formulation (% w/w) Formulation Drug No.Polymer BA BB EtOH Particles C_(max)/C_(min) T_(lag) 12^(1,a,IV,α,C) 3535 0 0 30 4.78 0.14 22^(1,a,IV,α,C) 35 35 0 0 30 9.86 0.1723^(1,a,IV,α,C) 35 0 35 0 30 6.83 0.17 29^(1,a,IV,χ,C) 31.5 0 34.65 3.8530 1.93 NV 32^(1,d,IV,α,C) 35 35 0 0 30 10.65 0.12 33^(1,f,IV,α,C) 35 035 0 30 6.35 0.14 35^(1,c,IV,α,C) 35 0 35 0 30 44.21 NV 55^(1,e,IV,α,C)35 0 35 0 30 6.33 0.11 56^(1,b,IV,ε,F) 38.5 0 31.5 0 30 17.10 NV60^(1,c,VI,α,C) 25 0 25 0 50 12.90 0.07 61^(1,c,IV,α,C) 35 0 35 0 3026.53 0.11 64^(4,c,VIII,α,C) 36.9 0 36.9 0 26.1 11.66 NV70^(4,c,VIII,α,C) 36.9 0 36.9 0 26.1 22.11 NV 1 = R209130, 2 = R167154,3 = risperidone base, 4 = risperidone pamoate, a = 50/50 PLGA-502 (MW =16,000), b = 50/50 PLGA-502H (MW = 11,000), c = 50/50 PLGA (MW = 6400),d = 40/55/5 PCL-GA-LA (MW = ~13,500), e = 75/25 PLGA (MW = 14,300), f =80/20 PCL-GA-LA/PVP, g = RG502:RG502H (1:1); α = P/S ratio of 50/50, β =P/S ratio of 40/60, χ = P/S ratio of 45/55, δ = P/S ratio of 60/40, ε =P/S ratio of 55/45; A = 63-125 μm, B = 20-63 μm, C = 75-125 μm, D = <38μm, E = micronized, F = as is, G = not applicable; NV = no valley

While the invention has been described with respect to a limited numberof embodiments, those skilled in the art, having benefit of thisdisclosure, will appreciate that other embodiments can be devised whichdo not depart from the scope of the invention as disclosed herein.

What is claimed is:
 1. An injectable depot formulation, comprising: abiocompatible polymer; an organic solvent combined with thebiocompatible polymer to form a viscous gel; and a small molecule drugincorporated in the viscous gel such that the formulation exhibits an invivo release profile having C_(max) to C_(min) ratio less than 200 andlag time less than 0.2.
 2. The formulation of claim 1, wherein the invivo release profile has C_(max) to C_(min) ratio less than
 30. 3. Theformulation of claim 1, wherein the small molecule drug is sparinglysoluble in water.
 4. The formulation of claim 1, wherein a solubility ofthe small molecule in water is less than 1 mg/ml.
 5. The formulation ofclaim 1, wherein the polymer is a polylactide.
 6. The formulation ofclaim 5, wherein the polymer has a monomer ratio of lactic acid toglycolic acid in the range from 100:0 to 15:85.
 7. The formulation ofclaim 1, wherein the polymer is selected from the group consisting ofpolylactides, polyglycolides, polycaprolactones, polyanhydrides,polyamines, polyurethanes, polyesteramides, polyorthoesters,polydioxanones, polyacetals, polyketals, polycarbonates,polyorthocarbonates, polyphosphazenes, succinates, poly(malic acid),poly(amino acids), polyvinylpyrrolidone, polyethylene glycol,polyhydroxycellulose, polysaccharides, chitin, chitosan, and copolymers,terpolymers and mixtures thereof.
 8. The formulation of claim 1, whereinthe solvent is selected from the group consisting of benzyl alcohol,benzyl benzoate, ethyl benzoate, ethyl hydroxide, triacetin,N-methyl-2-pyrrolidone, and mixtures thereof.
 9. The formulation ofclaim 1, wherein the small molecule drug comprises an antipsychoticagent.
 10. The formulation of claim 1, wherein the small molecule drugis selected from the group consisting of dopamine receptor agonist,dopamine receptor antagonist, serotonin receptor agonist, serotoninreceptor antagonist, serotonin uptake inhibitor, and combinationsthereof.
 11. The formulation of claim 1, wherein the small molecule drugis selected from the group consisting of base and salt forms of R209130and risperidone.
 12. The formulation of claim 1, wherein the smallmolecule drug has a molecular weight in a range from 200 to 2,000Daltons.
 13. The formulation of claim 1, wherein the solvent has amiscibility in water less than 7% by weight.
 14. The formulation ofclaim 1, wherein the small molecule drug is in the form of particleshaving an average particle size in a range from 0.1 to 125 μm.
 15. Theformulation of claim 1, which releases the small molecule drug at ornear target rate over at least one week.
 16. The formulation of claim 1,which releases the small molecule drug at or near target rate for up toone month.
 17. A method of administering a small molecule drug to asubject in a controlled manner, comprising: implanting in the subject aneffective amount of an injectable depot formulation comprising abiocompatible polymer, an organic solvent combined with thebiocompatible polymer to form a viscous gel, and a small molecule drugincorporated in the viscous gel such that the formulation exhibits an invivo release profile having C_(max) to C_(min) ratio less than 200 andlag time less than 0.2.
 18. The method of claim 17, wherein the smallmolecule drug is delivered systemically in a controlled manner over arelease duration.
 19. The method of claim 17, wherein the releaseduration is at least one week.
 20. The method of claim 17, wherein thesmall molecule drug comprises an antipsychotic agent.